Hartsfield Syndrome

A number sign (#) is used with this entry because of evidence that Hartsfield syndrome (HRTFDS) is caused by heterozygous mutation in the FGFR1 gene (136350) on chromosome 8p11.

Description

Hartsfield syndrome classically refers to the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur (Vilain et al., 2009). The disorder involves midline and limb field defects (Zechi-Ceide et al., 2009).

See also ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC; 129900), which shows phenotypic similarities.

Clinical Features

Hartsfield et al. (1984) reported a male infant born with multiple congenital anomalies, including lobar holoprosencephaly, ectrodactyly, and cleft lip/palate, who died at age 7 days. He also had hypertelorism, depressed nose, low-set and posteriorly rotated ears, and craniosynostosis. Radiographic analysis showed loss of digits on both the hands and feet and absence of the right radius. Postmortem analysis of the brain showed only partial separation of the cerebral hemispheres, hypoplasia of the posterior corpus callosum, absence of the septum pellucidum, fusion of the frontal lobes, and absence of the olfactory bulbs and tracts.

Young et al. (1992) reported a male fetus with features similar to those reported in the affected infant by Hartsfield et al. (1984). Routine ultrasonography at age 18 weeks showed lobar holoprosencephaly and facial and limb abnormalities. Postmortem examination showed cleft lip and palate, telecanthus, low-set ears, and ectrodactyly with syndactyly of the hands and feet. The skull frontal bones were small, the forebrain was fused anteriorly, and the olfactory bulbs were absent.

Konig et al. (2003) described a male patient, born of healthy, unrelated parents, with lobar holoprosencephaly, ectrodactyly, and cleft lip/palate. In addition, the patient developed hypernatremia and severe psychomotor retardation. Konig et al. (2003) identified 6 previously reported cases, all sporadic. They noted phenotypic overlap with the EEC syndrome (see 129900).

Vilain et al. (2009) reported 5 unrelated males with a phenotype most consistent with a diagnosis of Hartsfield syndrome. One was terminated as a fetus, and the others had mental retardation. One patient had arhinencephaly, a mild expression of the holoprosencephaly, and vermian hypoplasia. The 4 other patients had semilobar or lobar holoprosencephaly and hypoplasia or agenesis of the corpus callosum. Four had cleft lip and or palate. All patients had ectrodactyly, which was variable and ranged from 1 or 2 digits on the hands and feet to only duplicated thumbs. Two patients had central diabetes insipidus and hypogonadotropic hypogonadism. Variable features included hyper- or hypotelorism, abnormalities of ear morphology, and cryptorchidism, All patients had a normal karyotype. In a review of the 11 patients reported in the literature, Vilain et al. (2009) noted the variable phenotypic expression, but stated that holoprosencephaly and ectrodactyly are the only constant dysmorphic findings.

Zechi-Ceide et al. (2009) reported an affected 3-year-old boy. As an infant, he had a broad nasal bridge, megalocornea, cleft lip/palate, prominent ears, ectopic testes, and small penis. There were multiple digital anomalies: in the hand, the left second and third digits and the right third digit were hypoplastic; both feet had 3 toes, large halluces, and complete 4/5 cutaneous syndactyly. He showed poor growth and severe psychomotor retardation with no language development and poor head control at age 3 years. Skeletal studies showed multiple abnormalities of the bones of the hands, wrist, and feet, as well as absence of posterior arches of T1-T3 of the spine. Brain MRI showed semilobar holoprosencephaly with fusion of the frontal lobes, absence of the frontal horns of the lateral ventricles, abnormal frontal lobe gyration, agenesis of the corpus callosum, abnormal basal ganglia, and a hypoplastic brain stem.

Inheritance

Konig et al. (2003) noted that all 7 reported patients with holoprosencephaly, bilateral cleft lip/palate, and ectrodactyly were male, pointing to X-linked inheritance. However, autosomal dominant inheritance was demonstrated by Simonis et al. (2013) (see MOLECULAR GENETICS).

Molecular Genetics

Simonis et al. (2013) performed exome sequencing in 4 of the unrelated male patients with Hartsfield syndrome previously reported by Vilain et al. (2009) and identified missense mutations in the FGFR1 gene (see, e.g., 136350.0030 and 136350.0031) in all 4 patients. Sequencing of the FGFR1 gene in another male patient and a female patient with Hartsfield syndrome as well as in a female fetus with features of the disorder revealed mutations in the 2 patients (see, e.g., 136350.0032) but not in the female fetus. Simonis et al. (2013) noted that the fetus exhibited features that deviated substantially from those of FGFR1 mutation-positive patients with Hartsfield syndrome and might represent another diagnostic entity. Two of the patients were homozygotes; the parents of 1 of these patients were found to be heterozygous for the mutation (see 136350.0031) and were reportedly asymptomatic and spontaneously fertile. The parents of the other homozygote were unavailable for testing. Simonis et al. (2013) concluded that FGFR1 is the most prevalent, if not the sole gene causing Hartsfield syndrome.

Exclusion Studies

In the affected male they reported, Konig et al. (2003) excluded mutation in regions of the p63 gene (603273) in which mutations had been identified in EEC3 (604292).

In a patient with the disorder, Zechi-Ceide et al. (2009) excluded mutations in the SHH (600725), TGIF (602630), SIX3 (603714), GLI2 (165230), TP73L (603273), and DHCR7 (602858) genes.